By Summer Freeman
St. Jude Children’s Research Hospital scientists tie low levels of a key DNA repair protein to loss of regulatory genes in a study that offers new clues about why acute lymphoblastic leukemia sometimes returns
A newly identified defect in a DNA repair system might leave some young leukemia patients less likely to benefit from a key chemotherapy drug, possibly putting them at greater risk of relapse. The problem was identified in a study led by St. Jude Children’s Research Hospital scientists.
The study’s findings offer a potential new marker to help identify acute lymphoblastic leukemia (ALL) patients who are at higher risk of having their cancer return and thus are candidates for more tailored therapies. The research was published in the September 25 online edition of the scientific journal Nature Medicine.
The work focused on a protein named MSH2, which is involved in DNA repair. DNA is the molecule that carries instructions for building and sustaining life. Cell division requires DNA synthesis. The DNA repair system helps correct errors in DNA production. The DNA repair proteins are also involved in how some chemotherapy agents kill leukemia cells.
In this study, investigators discovered a new mechanism responsible for low MSH2 levels in about 11 percent of pediatric ALL and in several adult cancers. Researchers also found low MSH2 levels were associated with leukemia resistance to the thiopurine medications, including mercaptopurine, a drug all children with ALL receive.
“If confirmed, this work suggests a patient’s MSH2 status might someday be used to guide treatment,” said Barthelemy Diouf, Ph.D., the first author. He is a postdoctoral fellow in the laboratory of William Evans, Pharm.D., the paper’s senior author. Evans is chief executive officer and director of St. Jude.
In the U.S., ALL is diagnosed in about 3,000 children annually, making it the nation’s most common childhood cancer. It is also one of modern medicine’s success stories. At St. Jude, 90 percent of young ALL patients are now cured. This study reflects ongoing efforts to understand why treatment sometimes fails.
The research built on earlier work from the laboratory of Evans and others that linked a deficit of MSH2 with an increased risk of certain cancers and resistance to mercaptopurine, a drug that is the backbone of leukemia treatment.